chr12-13611833-C-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP2PP3PP5_Very_Strong

The NM_000834.5(GRIN2B):c.1672G>A(p.Val558Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GRIN2B
NM_000834.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8U:1

Conservation

PhyloP100: 7.87

Variant links:

Genes affected

GRIN2B (HGNC:4586): (glutamate ionotropic receptor NMDA type subunit 2B) This gene encodes a member of the N-methyl-D-aspartate (NMDA) receptor family within the ionotropic glutamate receptor superfamily. The encoded protein is a subunit of the NMDA receptor ion channel which acts as an agonist binding site for glutamate. The NMDA receptors mediate a slow calcium-permeable component of excitatory synaptic transmission in the central nervous system. The NMDA receptors are heterotetramers of seven genetically encoded, differentially expressed subunits including NR1 (GRIN1), NR2 (GRIN2A, GRIN2B, GRIN2C, or GRIN2D) and NR3 (GRIN3A or GRIN3B). The early expression of this gene in development suggests a role in brain development, circuit formation, synaptic plasticity, and cellular migration and differentiation. Naturally occurring mutations within this gene are associated with neurodevelopmental disorders including autism spectrum disorder, attention deficit hyperactivity disorder, epilepsy, and schizophrenia. [provided by RefSeq, Aug 2017]

GRIN2B links:

ENSG00000287928 (HGNC:):

ENSG00000287928 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the GRIN2B gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 135 curated pathogenic missense variants (we use a threshold of 10). The gene has 118 curated benign missense variants. Gene score misZ: 5.4168 (above the threshold of 3.09). Trascript score misZ: 7.3273 (above the threshold of 3.09). GenCC associations: The gene is linked to autism susceptibility 1, developmental and epileptic encephalopathy, 27, autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, West syndrome, intellectual disability, autosomal dominant 6.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.768

PP5

Variant 12-13611833-C-T is Pathogenic according to our data. Variant chr12-13611833-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-13611833-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GRIN2B	NM_000834.5 link	c.1672G>A	p.Val558Ile	missense_variant	Exon 9 of 14	ENST00000609686.4	NP_000825.2	Q13224A0A8D9PHB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GRIN2B	ENST00000609686.4 link	c.1672G>A	p.Val558Ile	missense_variant	Exon 9 of 14	1	NM_000834.5	ENSP00000477455.1		Q13224
ENSG00000287928	ENST00000652867.1 link	n.203-3265C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461432

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727058

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 6

Pathogenic:3

Apr 04, 2017

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed). -

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

See cases

Pathogenic:1

Nov 23, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS4, PM2, PM6, PP2, BP4 -

Intellectual disability, autosomal dominant 6;C4015316:Developmental and epileptic encephalopathy, 27

Pathogenic:1

Jan 26, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this missense change affects GRIN2B function (PMID: 28377535, 29681796). This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 558 of the GRIN2B protein (p.Val558Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant intellectual disability (PMID: 28377535). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 374243). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GRIN2B protein function. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:1

Aug 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate that V558I affected some GluN2B containing NMDAR channel property (Vyklivky et al., 2018); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28867141, 29681796, 28377535, 27839871) -

Complex neurodevelopmental disorder

Pathogenic:1

Dec 23, 2015

GenomeConnect - Simons Searchlight

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2015-12-23 and interpreted as Likely Pathogenic. Variant was initially reported on 2015-10-08 by GTR ID of laboratory name 279559. The reporting laboratory might also submit to ClinVar. -

intellectual deficiency

Pathogenic:1

Laboratory of Molecular Genetics, CHU Rennes

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

May 05, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.091

MetaRNN

Pathogenic

0.77

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.7

PrimateAI

Pathogenic

0.84

Sift4G

Uncertain

0.014

Polyphen

0.92

Vest4

0.65

MutPred

0.63

Loss of helix (P = 0.1299);

MVP

0.86

MPC

1.1

ClinPred

0.95

GERP RS

6.1

Varity_R

0.48

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over